Serotonin-Induced Hypercontraction Through 5-Hydroxytryptamine 1B Receptors in Atherosclerotic Rabbit Coronary Arteries

Abstract

Background —Augmented vasoconstriction to serotonin (5-hydroxytryptamine [5-HT]) in atherosclerotic vessels plays a crucial role in the development of myocardial ischemia. We investigated mechanisms for serotonin-evoked hypercontraction in atherosclerotic rabbit coronary arteries. Methods and Results —Contractile responses to serotonergic agents of endothelium-denuded coronary arteries from control and Watanabe heritable hyperlipidemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hypercontraction to 5-HT 1 –receptor agonists; the constrictor threshold concentrations and ED 50 to serotonin, 5-carboxamidotryptamine, and sumatriptan in WHHL were significantly lower, and the E max in WHHL to these agents were increased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT 1B/1D antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT 2 antagonist; 0.01 to 1 μmol/L), suggesting that the hypercontraction is most likely mediated by 5-HT 1B/1D receptors through a pertussis toxin–sensitive pathway. Furthermore, simultaneous measurements of [Ca 2+ ] i and isometric tension of fura-2–loaded arteries revealed that the hypercontraction was concomitant with the augmented elevation of [Ca 2+ ] i in the smooth muscle. The 5-HT 1B mRNA levels in WHHL coronary arteries increased to 2.5-fold over those in control arteries, whereas neither 5-HT 1D nor 5-HT 2A mRNA was detected in either group. Conclusions —Atherosclerotic rabbit coronary arteries exhibited the enhancement in contraction and Ca 2+ mobilization in response to serotonin. The 5-HT 1B receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.